Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of de-novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). Despite remarkable progress in the treatment of this disease, a significant fraction of DLBCL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for disease development and that can be targeted therapeutically. By integrating whole exome sequencing and high-resolution single nucleotide polymorphism array analysis, we have identified recurrent inactivating mutations and deletions of CREBBP (CBP) and, more rarely, EP300 (p300) in a large fraction of DLBCL patients, including 40% of those diagnosed de novo and ~50% of those derived from transformation of FL (Pasqualucci et al., Nature 2011; Pasqualucci et al., Cell Reports 2014). CBP and p300 are two highly related histone and non-histone acetyltransferases (HATs) and are involved in multiple signaling pathways by modulating the activity of several proteins, such as the oncoprotein BCL6, which is typically inactivated by acetylation, and the tumor suppressor p53, which instead requires acetylation for its function. Defects in CBP and p300 may therefore play a central role in promoting the development and maintenance of lymphoma cells. Following on these findings, the general objective of this proposal is to elucidate the normal and pathologic role of CBP and p300 in B cells, to establish pre-clinical models for their therapeutic targeting, and to test the activity of the novel HDAC inhibitor Mocetinostat in a phase II clinical trial. The following Specific Aims will be pursued: 1). Identify the full complement of genetic and epigenetic lesions affecting CBP/p300 in DLBCL, as a pre-requisite to design an optimal stratification strategy for the clinical trials proposed in Specific Aim 4. 2). Identify biomarkers of CBP/p300 activity (and loss thereof) by defining the set of genes that are bound by CBP and whose expression is modulated by CBP/p300 inactivation in GC B cells. 3). Elucidate the role of CBP inactivation in normal B cell development and transformation, by constructing mutant mice in which CBP is conditionally inactivated in GC B cells and which could be used as preclinical models for therapeutic testing. 4). Investigate whether pharmacologic inhibition of specific deacetylases in DLBCL patients with CBP/p300 inactivation predicts improved clinical efficacy of deacetylase inhibitors, either alone or in combination with other drugs.